Xerostomia is defined as dry mouth and/or thickened saliva resulting from altered, reduced or absent saliva flow. Saliva is a viscous clear fluid secreted from the salivary glands, which include for example the parotid, submaxillary, sublingual and smaller mucous glands in the oral cavity. Saliva is made up of various enzymes, proteins, small organic molecules, electrolytes and constituents of nonsalivary origin in a water matrix. Saliva possesses many important functions including antimicrobial activity, mechanical cleansing properties, maintaining oral pH between 6 and 7.4, removal of food from the oral cavity, lubrication of the oral cavity, remineralization and maintenance of the oral mucosa integrity. Saliva also provides a first defense against chemical, microbial and infectious attack.
Common causes of xerostomia include medications, irradiation of the head and neck and organic and psychogenic diseases. Some classes of medications that may cause xerostomia include anorectics, anticholinergics, antidepressants, antihistamines, antihypertensives, antiparkinson medications, antipsychotics, antispasmodics, decongestants, diuretics, sedative/hypnotics and narcotic analgesics. Approximately 1800 drugs in 80 drug classes have been reported to possess the capacity to cause xerostomia. Of the 50 most frequently prescribed brand name drugs in the U.S. in 2003, 64% were reported to be xerogenic. Xerostomia can effect patients in all age groups however, it is important to point out that it is the elderly population (described as individuals who are older than 65 years of age) who are most affected, because of their proportionally higher use of these types of drugs, often on a daily basis.
Sjögren's syndrome (SS) is reported as the most common disease causing xerostomia. SS is a chronic inflammatory disease that largely affects post menopausal women. Other rheumatoid conditions that may cause SS include rheumatoid arthritis, systemic lupus erythematosus and scleroderma. Organic diseases that have been reported to cause xerostomia include diabetes mellitus, hypertension, cystic fibrosis and neurological diseases such as Bell's palsy, cerebral palsy and trauma. Also, any condition that leads to dehydration has potential to produce xerostomia.
Radiotherapy plays a significant role in the management of head and neck cancer. An estimated 39,000 new cases of head and neck cancer occur annually in the U.S. and the incidence of xerostomia in those patients can exceed 80%. Acute oral mucositis and acute and chronic xerostomia are the most common and clinically significant toxicities arising from head and neck irradiation. Xerostomia can be a lifelong sequelae of head and neck radiation. It has been hypothesized that the irradiation of the head and neck may cause changes to the salivary glands that may or may not be permanent. Xerostomia has a clinically adverse impact on the patient and disrupts eating and sleeping as well as causing nausea.
Initial symptoms of xerostomia include problems eating, speaking and swallowing and a constant need for fluids. Chewing of dry foods may also become difficult. Patients with xerostomia complain of taste disorders, sore throat, burning sensations, increase in caries, inflammation of the gum line, and fissures of the lips. With prolonged and severe xerostomia chances of tooth loss with a risk of osteonecrosis greatly increase. As the oral mucosa becomes dehydrated, patients using dental appliances have problems with appliance retention, develop sores and complain of the tongue sticking to the palate of the mouth. As the oral pH decreases and the normal mouth flora are altered, the oral mucosa becomes dry and sticky and several opportunistic microorganisms increase in concentration, such as Candida albicans. 
The clinical diagnosis of xerostomia is usually made when the patient experiences dry mouth, thickened saliva, decreased salivary flow and a sudden onset of caries. The saliva may appear ropy and foamy on teeth and root surfaces.
Treatment of xerostomia has been directed toward the control of dental decay, relief of symptoms and increasing the saliva flow. The treatments available range from over the counter (OTC) medications to prescription drugs. Truly effective compounds appear to be few. As previously noted, a larger number of prescription drugs cause or exacerbate xerostomia. Fluoride gels and rinses are used to increase tooth resistance to caries by promoting remineralization of the teeth. Artificial saliva and saliva substitutes are used in the form of solutions, sprays and lozenges to replace moisture and lubricate the mouth, however, they must be used frequently and consistently as they do not stimulate salivary function. The prescription drugs available include pilocarpine, cevimeline, anethole trithione, yohimbine, human interferon alpha and amifostine. Pilocarpine (Salagen) is a cholingeric parasympathomimetic agent, which may stimulate salivary flow and produce clinical benefits in some patients as well as cause adverse effects with other drugs. Salagen dispensed in a tablet form stimulates salivary secretions but can also increase secretions from a number of other glands. Pilocarpine has been investigated for use as a treatment for oral mucositis but was found to be ineffective in the management of oral mucositis. Cevimeline a cholinergic agonist is another systemic agent that appears to help certain patient populations. Cevimeline, dispensed in a tablet form, stimulates salivary secretions but can result in excessive sweating and nausea. Anethole trithione is a cholagogue that stimulates salivary flow in drug-induced xerostomia. Some patients receiving the bile secretion-stimulating drug see improvements with salivary flow rates, trials in patients with SS show conflicting results. Yolimbine is an alpha-2 adrenergic antagonist that can increase saliva flow and maybe more effective than anethole trithione in SS populations. Human interferon alpha is currently in clinical trials for use as a primary treatment for SS. Amifostine (Ethyol) has been approved for use for the treatment of radiation-induced xerostomia, however, a study of this compound for the indication of oral mucositis found that amifostine did not reduce oral mucositis.
Even though there has been some success reported in treating xerostomia, as noted above, given the large number of patients suffering from xerostomia annually and the larger number of patients undergoing cancer therapy, who often receive multiple cycles of radiation therapy and/or chemotherapy, there is a significant need for improved treatments for xerostomia. The present invention is directed to this significant need.